The present invention relates to a process for the preparation of 4-[5-[bis(2-chloroethyl)amino]-1-methyl-1H-benzimidazol-2-yl]butanoic acid (9, Bendamustine) starting from 2-fluoro-5-nitroaniline and proceeding through the intermediates 5-(2-fluoro-5-nitroanilino)-5-oxopentanoic acid (1), 5-[2-(methylamino)-5-nitroanilino]-5-oxopentanoic acid (3) and 4-[5-[bis(2-hydroxyethyl)amino]-1-methyl-1H-benzimidazol-2-yl]butanoate (7) and a process for the preparation of said intermediate 4-[5-[bis(2-hydroxyethyl)amino]-1-methyl-1H-benzimidazol-2-yl]butanoate (7).
Bendamustine belongs to the alkylating agent class of compounds, in particular to the nitrogen mustard derivatives. As an antitumoral chemotherapeutic agent it is used both for the treatment of hematological tumours such as non-Hodgkin's and Hodgkin's lymphoma, mantle cell lymphoma, chronic lymphocytic leukaemia or multiple melanoma, as well as for the treatment of solid tumours such as breast cancer or small cell lung cancer.
The compound was first described in 1963 by Ozegowski and Krebs (see Ozegowski W, Krebs D. Aminosäureantagonisten. III. ω-[Bis-(β-chloräthyl)-amino-benzimidazolyl-(2)]-propion-bzw.-buttersäuren als potentielle Cytostatika. J. Prakt. Chem., 1963 Jun.; 20 (3-4): 178-186, and references cited therein) and was marketed under the name Cytostasan. In 1993, the compound was approved in Germany under the name Ribomustin. In 2008 the compound was approved by the FDA for the treatment of B-cell non-Hodgkin's lymphoma and chronic lymphocytic leukaemia under the trade name Treanda.
Numerous synthetic routes for the preparation of Bendamustine are known in the prior art.
Ozegowski et al. (1963) describe the synthesis of Bendamustine starting from N1-methyl-4-nitrobenzene-1,2-diamine.
The synthesis of Bendamustine starting from 1-methylamino-2,4-dinitrobenzene or 2,4-dinitroaniline is described in WO2010042568. The alkylation of the 1-methyl-5-amino-benzimidazole derivative to Bendamustine alkyl ester takes place directly to the crude Bendamustine alkylester with chloroacetic acid, chloroacetic acid ester or chloroacetaldehyde and subsequent reduction with borane-THF complex (reductive amination).
DD34727 describes a process for the preparation of N1-substituted derivatives of Bendamustine, wherein the alkylation of the 1-methyl-5-aminobenzimidazole derivative is performed with ethylene oxide.
WO2011079193 describes the alkylation of a 1-methyl-5-amino-benzimidazole derivative to the precursor of Bendamustine (bishydroxy compound) using 2-Haloethanols in the presence of an organic base.
An analogous alkylation of a 1-methyl-5-amino-benzimidazole derivative in the presence of inorganic bases such as sodium or potassium carbonate is described in WO2012007966 and IPCOM000185126D.
The known processes for the production of Bendamustine exhibit a number of disadvantages, such as the formation of by-products or low yields. In particular, the yield of the favoured procedure in WO2011079193 (using Hünig's base) is not greater than 44.5% and gives a purity of 97.6%.
Some reaction steps are not implementable in large scale or industrial processes. Often, ethylene oxide, a toxic and explosive gas, is used during the synthesis. The use of this gas is unfavourable for reasons of occupational safety.